Our previous work has demonstrated that 1) the hydroxylation of phenytoin to 5-phenl-5-para hydroxyphenyl hydantoin (HPPH) and the subsequent glucuronidation of HPPH are not altered by pregnancy whereas the biliary excretion of HPPH-glucuronide is markeldly inhibited and that 2) estradiol-17 beta-D-glucuronide is a potent cholestatic agent in the rat. The objectives in the proposed plan of research are to characterize the effect of pregnancy or estrogen-treatment in the rat on the following parameters: 1) the hydroxylation and/or glucuronidation of 14C-morphine and 14C-diazepam in the intact rat and in the isolated perfused liver (IPL). 2) the biliary excretion of 14C-HPPH-glucuronide, dibromophenolsulfophthalein (DBSP), 14C-morphine and 14C-diazepam in the bile-cannulated rat and in the IPL. 3) The rate constants for the transfer of DBSP from plasma to liver (k12), liver to plasma (k21) and liver to bile (k23) in the IPL and in bile cannulated rats. 4) The binding of 14C-HPPH-glucuronide, DBSP and bromophenolsulfophthalein to ligandin in hepatic cytosol. 5) Bile acid independent and bile acid dependent flow in the IPL and in bile-cannulated rats. In addition, the effect of conjugated estrogen metabolites on bile flow, bile salt excretion and canalicular bile production (as measured by erythritol clearance) in vivo and on Na ion K ion-ATPase in liver plasma membranes in vitro will be characterized.